Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to pharmaceutical compositions, which comprise compounds that act via antagonism of the CCR2b receptor for which MCP-1 is one of the known ligands and so may be used to treat inflammatory disease and/or neuropathic pain, which is mediated by these receptors.
• the invention further relates to novel compounds for use in the compositions, to processes for their preparation, to intermediates useful in their preparation and to their use as therapeutic agents.
• Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including rheumatoid arthritis, chronic obstructive pulmonary disease, atherosclerosis and other autoimmune pathologies such as inflammatory bowel disease, diabetes, asthma and allergic diseases. Chemokines also have a role in neuropathic pain, angiogenesis and modulation of chemokines may be beneficial in the treatment of cancer. Chemokines are small secreted molecules belonging to a growing superfamily of 8-14 kDa proteins characterized by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
• the C-C chemokines include potent chemoattractants of monocytes and lymphocytes such as monocyte chemoattractant proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on activation, Normal T expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP-1 ⁇ and MIP-1 ⁇ ).
• MCP-1, MCP-2 and MCP-3 monocyte chemoattractant proteins 1-3
• RANTES Registered on activation, Normal T expressed and Secreted
• eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP-1 ⁇ and MIP-1 ⁇ ).
• the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP 2).
• IL-8 interleukin-8
• NAP 2 neutrophil-activating peptide 2
• chemokines are mediated by subfamilies of G-protein coupled receptors, among which there are the receptors designated CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CX3CR1.
• the present invention relates to a compound of formula (I) as a base or as a pharmaceutically acceptable salt thereof,
• P is a phenyl or a monocyclic or bicyclic heteroaryl having up to 9 ring atoms and comprising up to 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or the heteroaryl is optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, phenyl, phenC 1-4 alkyl, phenC 1-4 alkoxy, phenC 1-4 alkoxyC 1-4 alkyl, heteroaryl, heteroC 1-4 alkyl, heteroC 1-3 alkoxy, and heteroC 1-4
• Another embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is a phenyl or a monocyclic heteroaryl having up to 9 ring atoms and comprising up to 3 heteroatoms independently selected from N, O and S, wherein the phenyl or the heteroaryl is optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, phenyl, phenC 1-4 alkyl, phenC 1-4 alkoxy, phenC 1-4 alkoxyC 1-4 alkyl,
• a further embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is a phenyl or a monocyclic heteroaryl having up to 9 ring atoms and comprising up to 3 heteroatoms independently selected from N, O and S, wherein the phenyl or the heteroaryl is optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, phenyl, phenC 1-4 alkyl, phenC 1-4 alkoxy, phenC 1-4 alkoxyC 1-4 alkyl
• a still further embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is phenyl optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, phenyl, phenC 1-4 alkyl, phenC 1-4 alkoxy, and phenC 1-4 alkoxyC 1-4 alkyl.
• a yet further embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is phenyl optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, and pentafluoroethyl.
• P is phenyl optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, and pentafluoroethy
• a still yet further embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is phenyl substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkylphenyl, and C 1-4 alkyl.
• P is phenyl
• said phenyl is substituted by 2 substituents selected from halogen.
• said halogens are selected from chloro and fluoro.
• Another embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is a monocyclic heteroaryl having up to 6 ring atoms and comprising up to 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, C 1-4 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, phenyl, phenC 1-4 alkyl, phenC 1-4 alkoxy, and phenC 1-4 alkoxyC 1-4 alkyl.
• said monocyclic heteroaryl is selected from furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, and pyrazinyl.
• said monocyclic heteroaryl is substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkylphenyl, and C 1-4 alkyl.
• Another embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein m is 0.
• Yet another embodiment relates to a compound according to formula (I) as a base or as a pharmaceutically acceptable salt thereof, wherein P is a phenyl or a monocyclic heteroaryl having up to 5 ring atoms and comprising up to 3 heteroatoms independently selected from N, O and S, wherein the phenyl or the heteroaryl is optionally substituted by up to 3 substituents independently selected from halogen, cyano, CF 3 , SC 1-4 haloalkyl, SC 1-4 alkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 alkylphenyl, and C 1-4 alkyl; and m is 0.
• the present invention also relates to a compound selected from 4-[(2R)-4-tert-butylpiperazine-2-carbonyl]-N[3(trifluoromethyl)phenyl]piperazine-1-carboxamide; 4-[(2R)-4-tert-butylpiperazine-2-carbonyl]-N-(3-chlorophenyl)piperazine-1-carboxamide; 4-[(2R)-4-tert-butylpiperazine-2-carbonyl]-N-[3-(trifluoromethylsulfanyl)phenyl]piperazine-1-carboxamide; N-(4-bromophenyl)-4-[(2R)-4-tert-butylpiperazine-2-carbonyl]piperazine-1-carboxamide; 4-[(2R)-4-tert-butylpiperazine-2-carbonyl]-N-[4-fluoro-3(trifluoromethyl)phenyl]piperazine-1-carbox
• Compounds of formula (I) as a base or a pharmaceutically acceptable salt thereof can be used in the treatment of diseases in which the chemokine receptor belongs to the C-C receptor subfamily.
• the target chemokine receptor is the CCR2 receptor.
• CCR2 is a receptor for the Monocyte chemoattractant protein-1 (MCP-1).
• MCP-1 is a member of the chemokine family of pro-inflammatory proteins that mediate leukocyte chemotaxis and activation.
• MCP-1 is a C-C chemokine that is a potent T-cell and monocyte chemoattractant.
• MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including, for example, rheumatoid arthritis, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel disease, and neuropathic pain.
• MCP-1 acts through the CCR2 receptor.
• MCP-2, MCP-3 and MCP-4 may also act, at least in part, through this receptor. Therefore in this specification, when reference is made to “inhibition or antagonism of MCP-1” or “MCP-1 mediated effects” this includes inhibition or antagonism of MCP-2 and/or MCP-3 and/or MCP-4 mediated effects when MCP-2 and/or MCP-3 and/or MCP-4 are acting through the CCR2 receptor.
• CCR2 is involved in neuropathic pain
• sensory nerve injury has been shown to increase both MCP-1 expression in dorsal root ganglia (DRG) sensory neurones [Tanaka et al, 2004, Zhang et al, 2006, WO2004/110376 A2, White et al, 2005b] and CCR2 expression in both neuronal and non-neuronal DRG cells [White et al, 2005b, WO2004/110376, Abbadie et al, 2003]. This results in two mechanisms by which CCR2 may modulate pain.
• DRG dorsal root ganglia
• the other mechanism is one in which elevated MCP-1 production from injured neurones recruits and/or activates CCR2+ immune cells. In turn, these CCR2+ immune cells in turn secrete pro-algesic substances that modulate pain processing.
• This indirect mechanism occurs both peripherally, where the CCR2+ cells are monocyte/macrophages, and centrally where the CCR2+ cells are microglial cells [Abbadie et al, 2003, Zhang et al 2007].
• C m-n or “C m-n group” refers to any group having m to n carbon atoms.
• alkyl used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
• C 1-6 alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
• a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group may be absent, i.e. there is a direct bond between the groups.
• alkoxy refers to radicals of the general formula —O—R, wherein R is selected from a hydrocarbon radical.
• R is selected from a hydrocarbon radical.
• C 1-6 alkoxy denotes alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms.
• alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and isobutoxy.
• alkenyl used alone or as a suffix or prefix, is intended to include both branched and straight chain aliphatic hydrocarbon groups comprising at least one carbon-carbon double bond (—C ⁇ C—) and having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
• C 2-6 alkenyl denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms.
• alkynyl As used herein, “alkynyl”, “, used alone or as a suffix or prefix, is intended to include both branched and straight chain aliphatic hydrocarbon groups comprising at least one carbon-carbon triple bond (—C ⁇ C—) and having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
• C 2-6 alkynyl denotes alkynyl having 2, 3, 4, 5 or 6 carbon atoms.
• halo includes fluoro, chloro, bromo and iodo.
• References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl.
• heterocyclyl includes aromatic or non-aromatic rings, or partially unsaturated ring systems, for example containing from 5-7 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur or nitrogen. Rings may be mono- or bi-cyclic. They may also contain bridges, in particular alkyl bridges.
• Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, tetrahydrofuryl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, indolinyl, benzimidazoly
• Heteroaryl refers to those heterocyclyl groups described above which has an aromatic character.
• aralkyl refers to aryl substituted alkyl groups such as benzyl.
• aryl and heteroaryl include non-condensed ring systems such as biphenyl.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
• a compound of the invention shows unexpected properties when compared to compounds disclosed in for example WO-2006/067401.
• a compound of the invention may have increased potency and/or increased margins vs hERG.
• PG is a protecting group, for example, benzyloxycarbonyl, benzyl or tert-butyloxycarbonyl with an isocyanate of Formula (III)
• the protecting group is benzyloxycarbonyl or benzyl then removal can be effected by hydrogenation (for example hydrogen in the presence of palladium on carbon catalyst).
• hydrogenation for example hydrogen in the presence of palladium on carbon catalyst.
• tert-butyloxycarbonyl removal may be effected by treatment with acid (such as hydrochloric acid or trifluoroacetic acid).
• the compounds of Formula I may be prepared as follows:
• a compound of formula (I), as a base or a pharmaceutically acceptable salt thereof, may be used in the treatment of:
• obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vascul
• Bone and joints arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective
• arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
• other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
• bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
• polychondritits such as osteoporosis, Paget'
• Skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma
• Eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; 6.
• Gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7.
• Abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8.
• nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. Allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10.
• CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
• Cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; 14.
• Oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and 15.
• Gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
• the invention further provides a compound of Formula (I) as defined above for use in the treatment of C-C-chemokine mediated disease such as inflammatory disease.
• C-C-chemokine mediated disease such as inflammatory disease.
• the compounds are suitably formulated into pharmaceutical compositions, which further contain a pharmaceutically acceptable carrier and these form a further aspect of the invention.
• the compound is conveniently used for the treatment of CCR2b mediated inflammatory diseases and/or neuropathic pain.
• the compounds of the present invention may be used in the treatment of neuropathic pain associated with a C-C chemokine mediated disease, condition or disorder such as those listed hereinbefore.
• compounds of the invention may be used in the treatment of neuropathic pain associated with a CCR2b chemokine mediated disease, condition or disorder.
• the compounds of the present invention may also be use in the treatment of acute pain, chronic pain, back pain, cancer pain, and visceral pain.
• Convenient examples include neuropathic pain associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease.
• inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease.
• COPD chronic obstructive pulmonary disease
• compounds of the invention may be used to treat neuropathic pain associated with arthritis and in particular osteoarthritis.
• the invention provides the use of a compound of Formula (I) as defined above in the preparation of a medicament for treating C-C chemokine mediated disease, and in particular for the treatment of CCR2b mediated inflammatory diseases.
• the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
• the compounds of the invention may be combined with agents listed below.
• Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular
• COX-2 inhibitors such
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
• a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
• the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax I1-15).
• B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax I1-15.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family.
• a modulator of chemokine receptor function such as an antagonist of CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
• MMPs matrix metalloprotease
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
• a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 Selected from the group consisting of the phenothiazin-3-1 s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
• phenothiazin-3-1 s such as L-651,392
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
• PDE phosphodiesterase
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
• a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
• a proton pump inhibitor such as omeprazole
• a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
• an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxy
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• M1, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
• a beta-adrenoceptor agonist including beta receptor subtypes 1-4
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
• a chromone such as sodium cromoglycate or nedocromil sodium.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs, for example rosiglitazone.
• PPARs nuclear hormone receptor
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof with gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof with celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
• an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
• a compound of the invention or a pharmaceutically acceptable salt thereof
• another systemic or topically-applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
• aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
• immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
• a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
• ACE angiotensin-converting enzyme
• angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
• a lipid lowering agent such as a statin or a fibrate
• a modulator of blood cell morphology such as
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
• a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, gabapentin, pregabalin, phenyloin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, CB1 agonist, muscarinic agonist, TRPV-1 antagonist, mGluR5 agonist or a non-steroidal anti-inflammatory agent.
• analgesic for example an opioid or derivative thereof
• carbamazepine for example an opioid or derivative thereof
• gabapentin gabapentin
• pregabalin pregabalin
• phenyloin sodium valproate
• amitryptiline or other anti-depressant agent-s paracetamol
• CB1 agonist muscarin
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
• a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
• a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
• an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine/threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (vii
• NKP-608C SB-233412 (talnetant) or D-4418
• elastase inhibitor such as UT-77 or ZD-0892
• TACE TNF-alpha converting enzyme inhibitor
• iNOS induced nitric oxide synthase
• chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
• inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
• TLR Toll-like receptors
• agent modulating the activity of purinergic receptors such as P2X7 or P2 ⁇ 3
• inhibitor of transcription factor activation such as NFkB, API, or STATS.
• a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
• an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
• the invention further relates to all tautomeric forms of the compounds of formula (IA) and pharmaceutical compositions containing these.
• compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intermuscular or intramuscular dosing or as a suppository for rectal dosing).
• oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
• compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
• Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
• inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
• granulating and disintegrating agents such as corn starch or algenic acid
• binding agents such as starch
• lubricating agents
• Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil such as peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• soft gelatin capsules in which the active ingredient is mixed with water or oil such as peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alg
• the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
• preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
• the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
• Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening, flavouring and preservative agents.
• Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
• sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
• compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
• a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
• Suppository formulations may be prepared by mixing the active ingredient with a is suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Suitable excipients include, for example, cocoa butter and polyethylene glycols.
• Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
• compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
• the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
• Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
• Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
• the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients, which may vary from about 5 to about 98 percent by weight of the total composition.
• Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
• a parenteral route is employed.
• a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
• a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
• Oral administration is however preferred.
• the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
• the compounds are useful in therapy for neuropathic pain.
• the compounds are useful in therapy for chronic neuropathic pain.
• the compounds of the present invention may be used to treat pain.
• the compounds of the present invention may be used to treat neuropathic pain.
• a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
• the compound of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally, intracerebroventricularly and by injection into the joints.
• any compound according to Formula (I) for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
• a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula (I) above, is administered to a patient in need of such therapy.
• the invention provides a method of treating inflammatory disease by administering a compound of Formula (I) as described above, or a pharmaceutical composition as described above.
• temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C.;
• organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60° C.;
• chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
• yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
• the LC comprised water symmetry 2 ⁇ 50 column C18 with 5 micron particle size.
• the eluents were: A, water with 0.1% formic acid and B, acetonitrile with 0.1% formic acid.
• the eluent gradient went from 95% A to 95% B in 5 minutes.
• N-(5-chloro-4-ethyl-1,3-thiazol-2-yl)piperazine-1-carboxamide (398 mg) was added to a stirred solution of (2R)-4-tert-butyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid (416 mg) in THF (10 ml).
• HOBT 222 mg
• EDCI 277 mg
• DIPEA 253 ⁇ l
• Step 5 Preparation of tert-butyl-2-(4-benzylpiperazine-1-carbonyl)-4-tert-butylpiperazine-1-carboxylate
• Step 1 Preparation of tert-butyl 4-(2-cyanopropan-2-yl)piperazine-1-carboxylate
• Methylmagnesiumbromide (3M in diethylether) (317 ml, 3.0 eq) was added dropwise over 30 minutes to a solution of tert-butyl 4-(2-cyanopropan-2-yl)piperazine-1-carboxylate (80 g, 1.0 eq) in THF (800 ml) at 15° C., exotherm seen 15° C.-28° C.
• THF 800 ml
• the reaction mixture was left stirred at room temperature for 18 hours.
• the reaction was cooled to ⁇ 10° C. and water (800 ml) was added dropwise over 60 minutes (very exothermic ⁇ 10° C.-25° C.).
• Step 4 preparation of tert-butyl (2R)-2-(4-benzylpiperazine-1-carbonyl)-4-tert-butylpiperazine-1-carboxylate
• Step 5 Preparation of tert-butyl (2R)-4-tert-butyl-2-(piperazine-1-carbonyl)piperazine-1-carboxylate
• rats are individually placed in Plexiglas boxes on a glass surface (maintained at 30° C.) of the paw thermal stimulator system (IITC Life Science, Woodland Hills, USA, Model 390, Series 8), and allowed to acclimatize for 30 minutes.
• a thermal stimulus in the form of a radiant heat beam, is focused onto the plantar surface of the affected paw.
• rats are tested twice approximately 5 minutes apart.
• Paw withdrawal latencies PWLs
• An assay cut off is set at 20 seconds. In all experiments, animals are tested before drug administration to ensure stable heat-hyperalgesia baseline.
• a study typically consists of 5 groups. One group is na ⁇ ve and serves as a baseline control. The other 4 groups undergo surgery to induce nerve injury. One of the groups serves as a vehicle control while the remaining 3 groups are treated with drug of increasing dose concentration. Test compound is administered orally and is tested for heat and/or mechanical hyperalgesia 240 minutes later. In all cases, the experimenter is blind to the treatment.
• Satellite animals are used for plasma and brain tissue collection. Animals are injected with drug but were not subjected to any testing. Blood and brain are collected by decapitation without anesthesia at the appropriate time point.
• % anti-hyperalgesia (PWL or PWT (dosed) ⁇ PWL or PWT (vehicle))/(PWL or PWT (na ⁇ ve) ⁇ PWL or PWT (vehicle)) ⁇ 100.
• THP1 cells were grown in RPMI (Sigma) supplemented with 10% foetal calf serum, 2 mM glutamine (Gibco), 100 units/ml Penicillin and 100 ⁇ g/ml Streptomycin (Invitrogen).
• Membrane fragments were prepared using cell lysis/differential centrifugation methods as described previously (Siciliano et al., 1990 , J. Biol. Chem., 265, 19688). Protein concentration was estimated by BCA protein assay (Pierce, Rockford, Ill.) according to the manufacturer's instructions.
• 125 I-labeled MCP-1 was prepared using Bolton and Hunter conjugation (Bolton et al., 1973 , Biochem. J., 133, 529; Amersham International plc).
• Test compounds were dissolved in DMSO and further diluted in assay buffer (50 mM HEPES, 1 mM CaCl 2 , 5 mM MgCl 2 , 1 mM EDTA, 0.03% BSA, pH 7.2) to give a range of concentrations starting with a top final concentration of up to 10 ⁇ M. All incubations had a 100 ⁇ l final volume and a DMSO concentration of 1%. Incubations contained 250 pM 125 I-labeled MCP-1 (GE Healthcare), 0.5 mg Scintillation proximity assay beads (GE Healthcare RPNQ001) and cell membranes containing 6 ⁇ 10 6 cells/ml equivalent.
• assay buffer 50 mM HEPES, 1 mM CaCl 2 , 5 mM MgCl 2 , 1 mM EDTA, 0.03% BSA, pH 7.2
• Non-specific binding was determined by the inclusion of 10 ⁇ M of a known CCR2b antagonist in the place of test compound. Total binding was determined in the presence of 1% DMSO without compound. Incubations were performed in sealed optiplates and kept at room temperature for 16 hours after which the plates were counted on a Packard TopCount (Packard TopCountTM). Dose-response curves were generated using “in-house” data analysis package incorporating Origin software to determine IC 50 values. Percent inhibitions were calculated for single concentrations of compound by using the following formula 100 ⁇ ((compound binding minus non-specific binding)/(total binding minus non-specific binding) ⁇ 100).

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• 2009
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• 2012
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• 2013
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